The present invention relates to a new methylidene malonate-based material for the suture of wounds.
Within the present description, the term xe2x80x9csuture materialxe2x80x9d refers to a bicompatible material that, by adhesion, lets the sides of wounds be brought together, stops bleeding (hemostasis) and favours the cicatrisation of injured tissue.
The invention mainly applies to the treatment of epidermic, dermo-epidermic or hypo-dermo-epidermic wounds, in particular clean dermo-epidermic wounds.
There are now four main ways for doctors to treat dermo-epidermic wounds, suture by resorbable or non-resorbable thread (stitches), the use of staples, the use of adhesive strips or the use of cutaneous glues.
Suture with thread is generally used to bring together the superficial dermic and epidermic layers, in the case of non resorbable thread, or to bring together the deep muscular and hypodermic layers in the case of resorbable thread.
This is the method of treatment most commonly used.
However, it is relatively difficult to use since it requires a local anaesthetic, sterile associated instruments (forceps, scissors, needle holder . . . ), nursing care after the treatment as well as the removal of the stitches several days later.
Although this is not too limiting during the post-surgical period, this is not the case during the treatment of post-traumatic wounds in the doctor""s office or emergency ward.
In addition, this type of treatment is more or less psychologically traumatic for the patient, especially if the patient is a child, in which case fast and painless treatment is warranted.
In practice, the use of staples pretty much involves the same problems as the suture with thread.
The use of adhesive strips, such as for example the product known under the trade name Steri-Strip(copyright) is used to treat benign wounds almost without pain.
However, its use is limited to the treatment of small dermo-epidermic wounds (about one centimeter) outside of any body area likely to be subject to mechanical stress.
Over the last few years, different adhesive biocompatible materials have been developed for the suture of wounds.
These adhesive materials are generally called xe2x80x9cgluesxe2x80x9d and can be divided into two categories:
biological adhesives, generally synthesised from plasma proteins;
synthetic adhesives, mainly made of cyanoacrylate, and in particular, 2-octylcyanoacrylate, 2-ethylcyanoacrylate, 2-butylcyanoacrylate and 2-isobutylcyanoacrylate.
Biological adhesives were chosen to reproduce the last phase of coagulation and anchor the clot to the tissue by providing fibronectin (xe2x80x9cjunction proteinxe2x80x9d) on the cicatrisation sites.
These biological adhesives are particularly advantageous since they are used to again interlock the injured tissue and allow for the growth of the cicatrisation tissue.
However, the main disadvantage is the underlying risk of viral transmission.
Synthetic adhesives are particularly advantageous since:
they generally come in ready-to-use form;
they can be used to suture varying sizes of wounds (from about 1 to 10 cm); and
the aesthetic quality of the scars after suture appears as good as or better than the scars obtained with a suture by thread or staples.
However, the synthetic adhesives currently available on the market have a great many disadvantages.
First, the adhesives are generally liquid and, applied only on the surface, tend to drip beyond their zone of application.
Second, these adhesives are generally potentially allergenic and decompose with great difficulty in the organism, generally forming products considered to be toxic for the organism. This considerably limits their value.
In these conditions,he purpose of the present invention is to solve a technical problem consisting of the provision of a novel material for the suture of wounds, that is essentially synthetic, that has the same advantages as the aforementioned synthetic adhesives, that is easy to use, can decompose relatively easy in the organism without producing toxic products and that can be applied inside the wound in all of the layers of the damaged skin.
The present invention also aims at solving the aforementioned technical problem in a way applicable on an industrial scale.
It was discovered, and this is the basis of the present invention, that certain monomer and/or oligomer and/or polymer compositions made of methylidene malonate have all of the properties required, in particular in terms of bio-adhesion and viscosity before and/or after application, for the creation of new materials for the suture of wounds complying with this goal.
Therefore, according to a first aspect, the purpose of the present invention is a material for the suture of wounds consisting of a biocompatible, bio-adhesive mixture containing at least 50% by weight, and preferably 80% by weight of a methylidene malonate-based composition containing:
40 to 100% by weight, and preferably 50 to 100% by weight of one or more methylidene malonates of formula (I) 
xe2x80x83in which:
A and B independently represent a group (a) or (b): 
in which R1 and R2 independently represent a linear or branched alkyl group with 1 to 6 carbon atoms, and n is an integer from 1 to 5;
and/or one or more methylidene malonate oligomers with a molecular weight less than or equal to 6,000 and consisting of recurrent units of formula (II): 
in which A and B are as defined above;
0 to 60% by weight, and preferably 0 to 50% by weight of one or more methylidene malonate polymers with a molecular weight greater than 6,000 and consisting of recurrent units of formula (II).
According to a specific feature of the invention, in aforementioned formulae (I) and (II):
A represents a group (a) in which R1 represents an alkyl group with 1 to 6 carbon atoms, preferably an ethyl group,
B represents a group (b) in which R2 represents an alkyl group with 1 to 6 carbon atoms, preferably an ethyl group, and n is a number equal to 1.
In a preferred embodiment of the invention, the aforementioned methylidene malonate composition contains:
50 to 90% by weight of one or more methylidene malonate oligomers with a molecular weight less than or equal to 6,000, preferably less than or equal to 3,000 and consisting of recurrent units of formula (II),
10 to 50% by weight of one or more methylidene malonate polymers with a molecular weight greater than 6,000,
and the aforementioned material has a glass transition temperature that less than or equal to 0xc2x0 C., preferably between xe2x88x9210 and xe2x88x9235xc2x0 C., and still preferably between xe2x88x9220 and xe2x88x9230xc2x0 C.
This composition is novel as such and this application also aims at protecting it as a novel material.
In a currently preferred embodiment of the invention, the aforementioned methylidene malonate-based composition contains:
55 to 65% by weight of one or more methylidene malonate oligomers with a molecular weight less than or equal to 3,000, and preferably between 300 and 1,000 and consisting of recurrent units of formula (II),
35 to 45% by weight of one or more methylidene malonate polymers with a molecular weight greater than 6,000, preferably greater than 9,000, and preferably between 12,000 and 25,000.
Thereby, the material for the suture of wounds that complies with the present invention is essentially characterised by the fact that it mainly consists of a methylidene malonate-based composition that itself mainly consists of monomer(s) and/or oligomer(s) whose molecular weight is less than or equal to 6,000, preferably less than or equal to 3,000.
The viscosity and bio-adhesion (or bonding) properties of such a composition enables its use in the treatment of dermo-epidermic wounds, alone or in a mixture with other biocompatible compounds.
In particular, it has been observed that such a composition may be applied within the wound, without any persistent bleeding noted during adhesion, and without any inflammatory reaction noted after 10 days of adhesion.
In addition, the methylidene malonate-based compositions that can be used in the invention, are degradable by bio-erosion, releasing ethanol and glycolic acid that are generally not considered to be toxic for the organism. Glycolic acid even seems to act like a stimulator of cell growth.
These methylidene malonate-based compositions may be easily prepared by the skilled man, optionally by the simple mixing of these compounds prepared separately (monomer(s), oligomer(s), polymer(s)) in an appropriate solvent, and the subsequent evaporation of the solvent.
The methylidene malonate monomers can be prepared according to the method described in patent EP 0,283,346 corresponding to patents U.S. Pat. No. 4,931,584 and U.S. Pat. No. 5,142,098 herein incorporated by reference, after vacuum degassing by a pallet pump to constant weight in order to remove the polymerisation inhibitor (SO2).
Methylidene malonate oligomers and polymers can be synthesized by anionic or radical polymerisation from the aforementioned monomers.
In the case of preferred methylidene malonate-based compositions, that are formed from a mixture of oligomer(s) and polymer(s), these compositions may also be obtained in one single step. The relative proportions of constituents can be adjusted by varying the concentration in anionic or radical initiator in the polymerisation medium.
The skilled man can easily adjust the aforementioned physico-chemical characteristics of the methylidene malonate-based compositions, to obtain a material for the suture of wounds that has the required characteristics of bio-adhesion and viscosity.
As understood, the physico-chemical characteristics have to be adjusted according to the nature of all of the components in the suture material. The goal is to obtain a bio-adhesive material with the appropriate viscosity.
In general, the constituents of the material for the suture of wounds complying with the invention, other than the aforementioned methylidene malonate-based composition, may account for up to 50% of the weight of this material.
Of course, these constituents will be chosen so as to form, with the aforementioned methylidene malonate-based compositions, intimate mixtures with the desired characteristics of bio-adhesion and viscosity.
Preferably, when present, these constituents only account for about 1 to 20%, more preferably 1 to 10% by weight of the total weight of the suture material.
These constituents may be varied, from natural or synthetic origin.
By way of example of such constituents, mention will be made of:
soluble or insoluble substituted functionalised dextrans that are more particularly described in patents FR no 2,555,589 and FR no 2,461,724:
polycyanoacrylates, preferably polyalkylcyanoacrylates;
polyalkylmethylacrylates;
biocompatible polyurethanes;
polyoxyalkylenes;
polyaminoacids;
polylactates;
polylactate-co-glycolates;
polyvinylalcohols.
Additional preferred constituents are, for example, polyethylene glycol, a hydrophilic additive belonging to the family of polyoxyalkylenes able to play a role as plasticiser within the mixture, or even poly(lactide-co-glycolide), a biodegradable additive belonging to the family of polylactate-co-glycolates able to improve the biodegradability of the mixture.
In general, these constituents will be present within the suture material in the form of mixtures with the aforementioned methylidene malonate-based compositions.
It should be noted that, without leaving the context of the present invention, these constituents may also be found within the suture material in the form of monomer units in copolymers including methylidene malonate units of formula (II), as defined above.
These methylidene malonate copolymers can be prepared by the classic polymerisation techniques well-known to the person skilled in the art. Among them, mention is made of anionic polymerisation, radical polymerisation or even the technique of coupling the precursor sequences of the copolymer, these sequences having been adequately functionalised beforehand on the chain end.
In general, the monomer units forming the aforementioned constituents will be chosen from among the constituent monomer units of polyacrylates, polysaccharides, polyoxyalkylenes, polylactates and polylactate-co-glycolates.
Among the constituent monomer units of polysaccharides able to be used in the context of the invention, mention can in particular be made of the constituent monomer units of soluble or insoluble substituted functionalised dextrans that are in particular described in patents FR no 2,555,589 and FR no 2,461,724.
Among the constituent monomer units of polyacrylates able to be used in the context of the invention, mention will be made of alkylcyanoacrylates, alkyl methacrylates and itaconates.
In general, at least 50% of the monomer units of the methylidene malonate-based copolymers used in the present invention will consist of methylidene malonate units.
These copolymers may be random or present block or grafted structures.
The suture material complying with the present invention may, if necessary, include biocompatible products able to adjust its viscosity among the constituents, like, for example, plasticisers or even biocompatible products that improve the adhesion like, for example, so-called xe2x80x9ctackifyingxe2x80x9d resins.
Among the plasticisers suitable for the present invention, mention will be made, for example, of the esters derived from adipic acid, azelaic acid, citric acid, oleic acid, stearic acid, sebacic acid; polyethylene glycol.
Among the suitable tackifying resins which are suitable within the context of the present invention, mention the modified polyterpine or terpine resins, hydrocarbon resins, and mixtures of aromatic and aliphatic resins.
The suture material, in compliance with the present invention, may also include one or more active principles among the constituents, mainly chosen from among the local anaesthetics, such as lidocaine; bacteriostatic agents and antibiotic agents, such as, for example, streptomycin; analgesics, like, for example, ketoprofen.
According to a second aspect, the purpose of the present invention is a treatment method for epidermic, dermo-epidermic, hypo-dermo-epidermic wounds characterised in that it consists of applying a sufficient quantity of material for the suture of wounds within the aforementioned wound, as defined above, if necessary previously preheated to a temperature above the softening temperature.
In the case of the preferred materials, mainly consisting of methylidine malonate-based compositions formed from a mixture of oligomers and polymers with a glass transition temperature between 0 and xe2x88x9250xc2x0 C., the aforementioned preheating temperature is in the order of about 35xc2x0 C. to 47xc2x0 C.
As understood, the suture material complying with the present invention, will be packaged in a form enabling its application, like, for example, inside a self-heating syringe.